X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on iodinated and other contrast agents for medical imaging is provided by D. P. Swanson, et al, Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company.
Great Britain Patent No. 889339 describes an x-ray contrast composition comprising an iodinated benzoic acid derivative and a non-toxic carrier. The compounds collect in the gall bladder.
U.S. Patent No. 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the structure ##STR2## wherein R.sup.1 is H or lower alkyl; R.sup.2 is H or lower alkanoyl; R.sup.3 is H or lower alkanoylamino and R.sup.4 is lower alkyl. The agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered orally, in the free acid form or in the form of a non-toxic salt, or intravenously, in the form of a water soluble, non-toxic salt. Example 15 therein describes ethyl 2-[3,5bis(acetylamino)]-2,4,6-triiodobenzoyloxy)hexanoate, i.e., ##STR3##
Bacon et al, commonly assigned U.S. patent application Ser. No. 07/990,897 filed Dec. 16, 1992 describes iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging compositions and methods. However, all of the compounds described by Bacon et al feature an ester group linked through a C.sub.2 or higher alkylene group to another ester group on an iodinated aromatic ring.
U.S. Pat. No. 3,128,301 by Larson et al describes x-ray contrast agents having the structure: ##STR4## which contains a carboxylic ester group.
In "Preparation of 3,5-Diaminobenzyl Alcohol and Its Iodinated Derivatives," Hebbky and Polacek, Collection Czechoslov. Chem. Common, 1970, 35 (2), 667-74 the preparation the 3,5 diaminobenzyl alcohol precursor for a 3,5-bis(diacethylamino)-2,4,6-triodobenzyl chloride compound is disclosed.
U.S. Pat. No. 5,322,679 by Bacon et al describes nanoparticulate x-ray contrast agents having the structure: ##STR5##
EP-A-498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging. The compositions comprise particles of an organic x-ray contrast agent and a surface modifier adsorbed on the surface thereof and have an effective average particle size of less than 400 nm. The agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes. Example 8, therein describes a formulation comprising ethyl 2-[3,5-bis(acetylamino)]-2,4,6-triiodobenzoyloxy) butyrate, i.e., ##STR6## wherein (Z)-COO is the residue of diatrizoic acid.
However, it has been discovered that ethyl 2-[3,5-bis(acetylamino)]-2,4,6-triiodobenzoyloxy) butyrate exhibits multiple crystal forms, i.e., polymorphs, e.g., when recrystallized from various solvents. The reasons that this behavior are not completely understood but, in any event, multiple crystal forms are disadvantageous for a variety of reasons. For example, the presence of multiple crystal forms renders scale up problematic due to the lack of reproducibility of the results obtained, including, e.g., in chemical manufacturing and in the milling process. Additionally, it has been found the nanoparticulate formulations of ethyl 2-[3,5-bis(acetylamino)]-2,4,6-triiodobenzoyloxy) butyrate do not exhibit good stability during autoclaving, i.e., conventional heat sterilization.
Consequently, it would be highly desirable to provide a poorly water soluble x-ray contrast agent having the advantages of ethyl 2-[3,5-bis(acetylamino)]-2,4,6-triiodobenzoyloxy) butyrate but which exhibits a consistent and reproducible crystal morphology, optimum hydrolysis, solubility and a high melting point is amenable to reproducible scale up and can be successfully heat sterilized by autoclaving to produce a stable and less toxic material.